Method for providing early onset of action in the treatment of rosacea

ABSTRACT

A regimen is described for providing early onset of action in the therapeutic treatment of rosacea including topically applying a pharmaceutical composition to the skin of a subject in need of said treatment. The pharmaceutical composition includes about 1% to about 10% benzoyl peroxide as the only active ingredient, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is applied once daily for a period of at least about 2, 4, 8 or 12 weeks. Based on early onset of action, a primary measure of success is at least about 9%, primary measure of success being defined as a 2-grade improvement in IGA of clear or almost clear; and a secondary measure of success is at least about 40%, secondary measure of success being defined as mean inflammatory lesion count percent reduction from baseline, after at least about 2 weeks of treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) from U.S.Provisional Application No. 62/977,974, filed Feb. 18, 2020, U.S.Provisional Application No. 62/977,952, filed Feb. 18, 2020, U.S.Provisional Application No. 62/972,896, filed Feb. 11, 2020, U.S.Provisional Application No. 62/972,310, filed Feb. 10, 2020, U.S.Provisional Application No. 62/960,384, filed Jan. 13, 2020, U.S.Provisional Application No. 62/925,258, filed Oct. 24, 2019, U.S.Provisional 62/871,286, filed Jul. 8, 2019, U.S. Provisional 62/871,283,filed Jul. 8, 2019, U.S. Provisional 62/807,356, filed Feb. 19, 2019,and U.S. Provisional 62/807,368, filed Feb. 19, 2019, the contents ofwhich are incorporated in their entirety as if fully set forth herein.

TECHNICAL FIELD

This application relates to methods for providing early onset of actionin the therapeutic treatment of skin conditions and afflictions, such asrosacea and symptoms and considerations associated therewith, includingtopically applying to the skin of a subject in need of said treatment apharmaceutical composition comprising benzoyl peroxide.

BACKGROUND

Rosacea is a chronic disease of inflammatory dermatitis that mainlyaffects the median part of the face and the eyelids of certain adults.It is characterized by telangiectatic erythema, dryness of the skin.papules and pustules. Conventionally, rosacea develops in adults fromthe ages of 30 to 50, and more frequently affects women, although thecondition is generally more severe in men. Rosacea is a primitivelyvascular condition whose inflammatory stage lacks the cysts andcomedones characteristic of common acne.

Factors that have been described as possibly contributing towards thedevelopment of rosacea include for example: the presence of parasitessuch as the Demodex folliculorum, the presence of bacteria such asHelicobacter pylori (a bacterium associated with gastrointestinaldisorders), hormonal factors (such as endocrine factors), climatic andimmunological factors, and so forth.

Rosacea develops in four stages over several years, in spasms aggravatedby variations in temperature, alcohol, spices, exposure to sunlight andstress. The various stages of the disease are:

Stage 1 (stage of erythema episodes): the patients have erythrosisspasms due to the sudden dilation of the arterioles of the face, whichthen take on a congestive, red appearance. These spasms are caused byemotions, meals and temperature changes.

Stage 2 (stage of couperosis, i.e., of permanent erythema withtelangiectasia): certain patients also have oedema on the cheeks and theforehead.

Stage 3 (inflammatory stage, papulopustular rosacea): patients exhibitappearance of inflammatory papules and pustules, but without affectingthe sebaceous follicles, and thus, with absence of cysts and comedones.

Stage 4 (rhinophyma stage): this late phase essentially affects men. Thepatients have a bumpy, voluminous red nose with sebaceous hyperplasiaand fibrous reordering of the connective tissue.

Typical treatment of rosacea includes oral or topical administration ofantibiotics such as tetracyclines, salicylic acid, anti-fungal agents,steroids, metronidazole (an anti-bacterial agent) and isotretinoin, oreven with anti-infectious agents such as azelaic acid.

SUMMARY

An exemplary embodiment of this application is a regimen for providingearly onset of action in the therapeutic treatment of rosacea, theregimen comprising topically applying to the skin of a subject in needof said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising from about 1% w/w to about 10% w/w benzoylperoxide as an active ingredient, and a pharmaceutically acceptablecarrier or excipient, wherein the benzoyl peroxide is the only activeingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 2, 4, 8 or 12 weeks, wherein a primary measure of success ina group of subject is at least about 9% after about 2 weeks, and whereinthe primary measure of success is defined as a 2-grade improvement inInvestigator Global Assessment (IGA) of clear or almost clear.

Another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a primary measure of success in a group of subject is atleast about 25% after about 4 weeks, and wherein the primary measure ofsuccess is defined as a 2-grade improvement in Investigator GlobalAssessment (IGA) of clear or almost clear.

Another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4 or 8 weeks,wherein a primary measure of success in a group of subject is at leastabout 40% after about 8 weeks, and wherein the primary measure ofsuccess is defined as a 2-grade improvement in Investigator GlobalAssessment (IGA) of clear or almost clear.

Another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a secondary measure of success in a group of suchsubjects is at least about 40% after at least about 2 weeks, and whereinthe second measure of success is defined as mean inflammatory lesioncount percent reduction from baseline.

Another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a secondary measure of success in a group of suchsubjects is at least about 55% after at least about 4 weeks, and whereinthe second measure of success is defined as mean inflammatory lesioncount percent reduction from baseline.

Another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a secondary measure of success in a group of suchsubjects is at least about 65% after at least about 8 weeks, and whereinthe second measure of success is defined as mean inflammatory lesioncount percent reduction from baseline.

Another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, and wherein the absolute reduction in lesion count after about 2weeks is at least twice the absolute reduction in lesion count afterabout 4 weeks of treatment.

Another exemplary embodiment of this application is a pharmaceuticalcomposition for use as a medicament for providing early onset of actionin the therapeutic treatment rosacea, the pharmaceutical compositioncomprising from about 1% w/w to about 10% w/w benzoyl peroxide as anactive ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a primary measure of success in a group of subject is atleast about 9% after about 2 weeks, and wherein the primary measure ofsuccess is defined as a 2-grade improvement in Investigator GlobalAssessment (IGA) of clear or almost clear.

Another exemplary embodiment of this application is the use of apharmaceutical composition for providing early onset of action in thetreatment of rosacea, the pharmaceutical composition comprising fromabout 1% w/w to about 10% w/w benzoyl peroxide as an active ingredient,and a pharmaceutically acceptable carrier or excipient, wherein thebenzoyl peroxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 2, 4, 8 or 12 weeks, wherein aprimary measure of success in a group of subject is at least about 9%after about 2 weeks, and wherein the primary measure of success isdefined as a 2-grade improvement in Investigator Global Assessment (IGA)of clear or almost clear.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject in need of said treatment duringthe duration of the regimen; the pharmaceutical composition comprisesabout 2.5% w/w to about 10% w/w of benzoyl peroxide, preferably about 5%w/w of benzoyl peroxide; the benzoyl peroxide is in a form selected fromsolid, solution or suspension; the regimen is a first-line therapy forthe treatment of rosacea; the rosacea is any of erythematotelengietatic,papulopustular, phymatous or ocular rosacea; the pharmaceuticalcomposition is a cream or an emulsion; the pharmaceutical composition isan extended release formulation; the extended-release effect is obtainedby encapsulation, microencapsulation, microspheres or coating,preferably the benzoyl peroxide is encapsulated and/or microencapsulatedand/or the benzoyl peroxide is included in a microsphere and/or acoating; and/or the regimen has an adverse events values similar to orlower than the adverse events values of a vehicle control.

In other exemplary embodiments, the reduction in total number ofinflammatory lesion counts in a group of such subjects is a reduction ofat least about 14 lesions after at least about 4 weeks of treatment;and/or the reduction in total number of inflammatory lesion counts in agroup of such subjects is a reduction of at least about 17 lesions afterat least about 8 weeks of treatment.

In other exemplary embodiments, the pharmaceutical composition can beused as a medicament in the first-line treatment of rosacea.

Details of other exemplary embodiments of the present disclosure will beincluded in the following detailed description and the accompanyingdrawings. It is appreciated that certain features of the exemplaryembodiments described in this application, which are, for clarity,described in the context of separate embodiments, can also be providedin combination in a single embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the disclosure and to see how it can be carriedout in practice, embodiments will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIG. 1 is a graph presenting the IGA per time of administering BPOcomposition as compared with vehicle alone over a period of time of 12weeks.

FIG. 2 is a graph presenting the percentage decrease in inflammatorylesion count per time of administering BPO composition as compared withvehicle alone over a period of time of 12 weeks.

FIG. 3 is a graph presenting the absolute decrease in inflammatorylesion count per time of administering BPO composition as compared withvehicle alone over a period of time of 12 weeks.

FIG. 4 is a graph presenting the difference in drug and vehicle IGA pertime of administering BPO composition according to exemplary embodimentsof this application as compared with the difference in drug and vehicleIGA per time of administering SOOLANTRA®.

DETAILED DESCRIPTION

Multiple studies have been directed to the treatment of rosacea using apharmaceutical or dermatological active agent such as metronidazole,azelaic acid, sulfacetamide, brimonidine, ivermectin, permethrin andclindamycin, and with doxycycline, which is identified as the onlyFDA-approved treatment for rosacea (Oge et al., “Rosacea: Diagnosis andTreatment,” American Family Physician, v. 92(3), pp. 187-198 (2015); Gulet al., “A case of granulomatous rosacea successfully treated withpimecrolimus cream,” J. Derm. Treatment, 19, 313-315 (2008)).

Benzoyl peroxide (BPO) is generally identified as an anti-acne agent,used alone (U.S. Pat. No. 9,439,857; Wester et al., “Controlled releaseof benzoyl peroxide from a porous microsphere polymeric system canreduce topical irritancy,” J. Am. Acad. Derma. 24, 720-726 (1991);Sawleshwarkar, “Multicenter study to evaluate efficacy and irritationpotential of benzoyl peroxide 4% cream in hydrophase base (Brevoxyl) inacne vulgaris,” Ind. J. Derm. Vener. Lepro., 69(1), 19-22 (2003)) or incombination with a primary active such as avermectin (U. S.2011/0052515).

One such study includes a therapeutic regimen involving treatment ofacne rosacea in a group of patients in need of such treatment with 5%BPO-acetone gel for four weeks, followed by treatment of the same groupof patients with 10% BPO-acetone gel for an additional four weeks.(Montes et al., “Topical Treatment of Acne Rosacea with Benzoyl PeroxideAcetone Gel,” Therapeutics for the Clinician: New Reports on TreatmentModalities of Possible Interest to Patient-Caring Physicians, 32,185-190 (1983)). The Montes study showed a significantly better responseduring the five to eight weeks of treatment with 10% BPO-acetone gelcompared to the first four weeks of treatment with 5% BPO-acetone gel.Moreover, although Montes 1983 claims success in the treatment ofrosacea using a BPO-acetone gel, 25% of the patients in the study showedno improvement and 40% of the patients developed an irritation.Additionally, this study required increasing the amount of BPOadministered to the patients from 5% to 10% after week four. The resultsof the Montes 1983 study make it clear that BPO would not be suitablefor regular use in the treatment of rosacea, especially as a first linetreatment of rosacea.

Other studies show that, when used in the treatment of rosacea, BPO isgenerally combined with a primary active agent such as clindamycin(Breneman et al., “Double-blind, randomized, vehicle-controlled clinicaltrial of once-daily benzoyl peroxide/clindamycin topical gel in thetreatment of patients with moderate to severe rosacea,” Int. J. Derm.,43, 381-387 (2004); Gold et al., “Use of Benzoyl Peroxide/Clindamycingel in the once daily treatment of moderate rosacea,” J. Amer. Acad.Dermat., 52(3), sup., P25 (2004); Leyden et al., “Blind photographicreview for a double blind, multicenter, placebo-controlled studycomparing Benzoyl Peroxide/Clindamycin and placebo for the treatment ofrosacea,” J. Amer. Acad. Dermat., 52(3), sup., P14 (2004); Goldgar etal., “Treatment Options for Acne Rosacea,” J. Amer. Fam. Physician,80(5), 461-468 (2009)).

BPO is generally identified as only a possible second-line treatment ofrosacea following the use of another, different active. (Oge 2015, Table5; Goldgar 2009, “Key Recommendations for Practice”). Goldgar 2009, inparticular, recommends the use of BPO only as a tertiary therapy for thetreatment of rosacea.

When BPO was used as the sole active agent for the treatment of rosacea,lesions were found to be unresponsive. (Gul 2008).

These previous rosacea treatments with BPO alone or in combination withother agents, have been shown to have severe drawbacks such asirritation and intolerance phenomena, especially when they areadministered for a prolonged period. (Crawford et al., “Rosacea: I.Etiology, pathogenesis, and subtype classification,” J. Am. AcadDermatol., 51, 327-341 (2004)). These treatments are only suppressiveand not curative, acting especially on the pustulous spasms occurringduring the inflammatory stage.

Such drawbacks associated with the treatment of rosacea involving theuse of BPO result in exclusion of BPO from standard rosacea treatmentmethods. For example, “A Review of the Current Modalities for theTreatment of Papulopustular Rosacea” identifies metronidazole,ivermectin and azelaic acid as topical therapies that were proveneffective for the treatment of rosacea. (McGregor et al., “A Review ofthe Current Modalities of the Treatment of Papulopustular Rosacea,”Dermatol. Clin. (2017)). While McGregor 2017 mentions alternatetherapies, such as sodium sulfacetanide/sulfur cream, clindamycin,tretinoin, calcineurin inhibitors and oral tretinoin, that may have someeffectiveness in the treatment of rosacea, notably, McGregor 2017 doesnot include, or even mention, BPO in the long list of possible treatmenttherapies described therein. The absence of BPO as a known treatment forrosacea is also evident in other studies. (Feaster et al., “Clinicaleffectiveness of novel rosacea therapies,” Current Op. Pharmacol., 46,14-18 (2019); Del Rosso et al., “Update on the Management of Rosaceafrom the American Acne & Rosacea Society (AARS); J. Clinical & AestheticDermat., 12 (6), 17-24 (2019)). The absence of BPO as a recognizedfirst-line treatment for rosacea is especially evident in Del Rosso,which is a well-known and respected authority on the treatment ofrosacea. The AARS review lists the Society's recommendation for rosaceatreatment, including topical metronidazole, topical azelaic acid, oraltetracyclines, ivermectin, topical alpha agonists, and oralisotretinoin, as well as “alternative therapies,” such assulfacetamide/sulfur, calcineurin inhibitors, retinoids, and permethrin.(See e.g., Table 1 of the AARS review.) BPO is not mentioned in the AARSreview either as a leading, or even an alternative, therapeutic agentfor the treatment of rosacea.

Considering the chronic nature of rosacea, there is a need for earlyonset of action, and a prolonged use treatment of the disease, itssymptoms and associated conditions, in a safe and effective manner.Thus, there exists a need for compositions that show early onset ofaction, and improved efficacy in the treatment of rosacea, that impartgreater tolerance to the active principles and that reduce,substantially minimize or do not have the side effects described in theprior art.

Advantages and features of the present disclosure, and methods foraccomplishing the same will be more clearly understood from exemplaryembodiments described below with reference to any accompanying drawings.However, the present disclosure is not limited to the followingexemplary embodiments and can be implemented in various different forms.The exemplary embodiments are provided only to provide sufficientdisclosure of the present discoveries and to fully provide a personhaving ordinary skill in the art to which the present disclosurepertains within the technical field, and the present disclosure will bedefined by any appended claims and combinations thereof.

As used herein, like reference numerals generally denote like elementsthroughout the present specification. Further, in the followingdescription, a detailed explanation of well-known related technologiescan be omitted to avoid unnecessarily obscuring the subject matter ofthe present disclosure.

As used herein, terms such as “including” and “having” are generallyintended to allow other components to be included unless the terms areused in conjunction with the term “only.”

As used herein, the term “topical use” is meant to encompass the topicaladministration of an exemplary composition by formulating saidcomposition in any way known in the art, or in formulations disclosedherein, which are compatible with the skin, mucous membranes and/or theinteguments.

As used herein, the term “treating” or “treatment” includes curing acondition, treating a condition, preventing or substantially preventinga condition, treating symptoms of a condition, curing symptoms of acondition, ameliorating, reducing and/or minimizing symptoms of acondition, treating effects of a condition, ameliorating, reducingand/or minimizing effects of a condition, and preventing and/orsubstantially preventing results of a condition,

As used herein, the term “first-line therapy” or “first-line treatment”means a therapy or treatment for which its label does not include arequirement or recommendation that said therapy or treatment should beused only after other therapies or treatments were shown to beunsatisfactory or unsuccessful. It can also include a therapy and/ortreatment wherein no other actives (beyond the main active) areadministered to the individual subject in need.

As used herein, the term “early onset” or “early onset of action” meansachieving a desired result and/or effect at a point in time that isearlier or even much early than achieved using a vehicle or other,conventional treatment approach. For example, it can mean achieving adesired result and/or effect no later than about 8 weeks from initialtreatment, preferably no later than about 4 weeks from initialtreatment, and more preferably no later than about 2 weeks from initialtreatment.

As used herein, the term “pharmaceutical composition” refers to acomposition comprising one or more active ingredients with othercomponents such as, for example, pharmaceutically acceptable ingredientsand/or excipients. The purpose of a pharmaceutical composition is tofacilitate administration of an active ingredient to a subject.

As used herein, the terms “pharmaceutically active agent” or “activeagent” or “active pharmaceutical ingredient” are interchangeable andmean the ingredient is a pharmaceutical drug, which is biologically-and/or chemically-active and is regulatory-approved or approvable assuch.

As used herein, the term “ingredient” refers to a pharmaceuticallyacceptable ingredient, which is included or is amenable to be includedin The FDA's Inactive Ingredient (IIG) database. Inactive ingredientscan sometimes exhibit some therapeutic effects, although they are notdrugs.

As used herein, the term “adverse events values” refers to an averagepercentage of subjects that experience any adverse events associatedwith the treatment of rosacea with a composition described and/orclaimed herein (usually on a surface of the skin of a subject treatedwith a composition described and/or claimed herein). A non-limiting listof such adverse events includes: irritation, dryness, scaling, itchingpurities, burning, stinging, combinations thereof and the like.

Whenever a numerical range is indicated herewith, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicated number and asecond indicated number and “ranging/ranges from” a first indicatednumber “to” a second indicated number are used herein interchangeableand are meant to include the first and second indicated numbers and allfractional and integral numerals therebetween.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “10 μm” is intended to mean“about 10 μm.”

As used herein, numbers and/or numerical ranges preceded by the term“about” should not be considered to be limited to the recited range.Rather, numbers and/or numerical ranges preceded by the term “about”should be understood to include a range accepted by those skilled in theart for any given element in formations according to the subjectinvention.

As used herein, when a numerical value is preceded by the term “about,”the term “about” is intended to indicate +/−10%.

As used herein, the singular form “a,” “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” can include a pluralityof compounds, including combinations and/or mixtures thereof.

As used herein, the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, technical and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

It is appreciated that certain features of the exemplary embodimentsdescribed herein, which are, for clarity, described in the context ofseparate embodiments, can also be provided in combination in a singleembodiment. Conversely, various features of the exemplary embodiments,which are, for brevity, described in the context of a single embodiment,can also be provided separately or in any suitable sub-combination or assuitable in any other described embodiment. Certain features describedin the context of various embodiments are not to be considered essentialfeatures of those embodiments, unless the embodiment is inoperativewithout those elements.

An exemplary embodiment of this application is regimen for thetherapeutic treatment of rosacea, the regimen comprising topicallyapplying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 1% w/w to about 10% w/w benzoyl peroxide as an active ingredient,and a pharmaceutically acceptable carrier or excipient, to achieve, in agroup of such subjects, a primary measure of success of at least about9%, wherein said pharmaceutical composition is applied once daily for aperiod of at least about 2 weeks, and wherein the primary measure ofsuccess is defined as a 2-grade improvement in Investigator GlobalAssessment (IGA) of clear or almost clear.

The success in IGA, a primary measure of success, after topicalapplication of BPO as a first-line of treatment for at least about 2weeks can be at least about 8%, preferably from about 9% to about 15%,and more preferably from about 9% to about 13%.

The success in IGA, a primary measure of success, after topicalapplication of a pharmaceutical composition including BPO as afirst-line of treatment for at least about 4 weeks can be at least 20%,preferably from about 20% to about 40%, preferably from about 25% to35%, preferably from about 25% to about 32%, and more preferably about25%.

The success in IGA, a primary measure of success, after topicalapplication of a pharmaceutical composition including BPO as afirst-line of treatment for at least about 8 weeks can be at least about30%, preferably from about 30% to about 50%, from about 35% to about45%, more preferably about 40%.

The success in IGA, a primary measure of success, after topicalapplication of a pharmaceutical composition including BPO as afirst-line of treatment for at least about 12 weeks can be at least atleast about 30%, preferably from about 30% to about 50%, from about 35%to about 50%, more preferably about 47%.

In another exemplary embodiment, the benzoyl peroxide is the only activeingredient in said pharmaceutical composition and/or in the regimenand/or in the method of treatment. In another exemplary embodiment, thebenzoyl peroxide is the sole active ingredient administered to thesubject during the duration of the regimen.

In another exemplary embodiment, the pharmaceutical compositioncomprises about 2.5% w/w to about 10% w/w of benzoyl peroxide,preferably about 3.0% to about 10% of benzoyl peroxide, more preferablyabout 3% to about 5% of benzoyl peroxide, and more preferably about 5%w/w of benzoyl peroxide.

In another exemplary embodiment, the benzoyl peroxide is in a formselected from solid, solution, and suspension.

In another exemplary embodiment, the regimen is a first-line therapy forthe treatment of rosacea.

In another exemplary embodiment, the rosacea is any oferythematotelengietatic, papulopustular, phymatous or ocular rosacea.

In another exemplary embodiment, the pharmaceutical composition is acream, cream gel, an emulsion, a gel or a foam; preferably a cream or anemulsion.

In another exemplary embodiment, the pharmaceutical composition can bean extended- and/or controlled-release formulation, and theextended-release and/or controlled-release effect is obtained by any oneof encapsulation, microencapsulation, microspheres and/or coating, orcan be encapsulated and/or microencapsulated or included in amicrosphere and/or a coating.

In another exemplary embodiment, the regimen surprisingly exhibitsadverse events values similar to, or even less than, the adverse eventsvalues of a vehicle control.

Yet another exemplary embodiment of this application is a regimen forthe therapeutic treatment of rosacea, which includes topically applyingto the skin of a subject in need of said treatment a pharmaceuticalcomposition including about 1% to about 10% benzoyl peroxide as anactive ingredient, and a pharmaceutically acceptable carrier orexcipient, to achieve, in a group of such subjects, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition and/or in said regimen.

Yet another exemplary embodiment of this application is a regimen forproviding early onset of action in the therapeutic treatment of rosacea,the regimen comprising topically applying to the skin of a subject inneed of said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% to about 10% benzoyl peroxide as anactive ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein said pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a secondary measure of success in a group of suchsubjects is at least about 40% at one of the corresponding time points,and wherein the second measure of success is defined as meaninflammatory lesion count percent reduction from previous measurement.

Yet another embodiment of this application is a regimen for providingearly onset of action in the therapeutic treatment of rosacea, theregimen comprising topically applying to the skin of a subject in needof the treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient inthe pharmaceutical composition, wherein the pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a secondary measure of success in a group of suchsubjects is at least about 55% after at least about 4 weeks, and whereinthe second measure of success is defined as mean inflammatory lesioncount percent reduction from baseline.

Yet another embodiment of this application is a regimen for providingearly onset of action in the therapeutic treatment of rosacea, theregimen comprising topically applying to the skin of a subject in needof the treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient inthe pharmaceutical composition, wherein the pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, wherein a secondary measure of success in a group of suchsubjects is at least about 65% after at least 8 weeks, and wherein thesecond measure of success is defined as mean inflammatory lesion countpercent reduction from baseline. In some embodiments, the benzoylperoxide is the sole active ingredient administered to the subject inneed of the treatment during the duration of the regimen. In someembodiments, the reduction in total number of inflammatory lesion countsin a group of such subjects is at least about 14 lesion reduction afterat least about 4 weeks of treatment. In some other embodiments, thereduction in total number of inflammatory lesion counts in a group ofsuch subjects is at least about 17 lesion reduction after at least 8weeks of treatment.

Yet another embodiment of this application is a regimen for providingearly onset of action in the therapeutic treatment of rosacea, theregimen comprising topically applying to the skin of a subject in needof said treatment a pharmaceutical composition, the pharmaceuticalcomposition comprising about 1% w/w to about 10% w/w benzoyl peroxide asan active ingredient, and a pharmaceutically acceptable carrier orexcipient, wherein the benzoyl peroxide is the only active ingredient insaid pharmaceutical composition, wherein the pharmaceutical compositionis applied once daily for a period of at least about 2, 4, 8 or 12weeks, and wherein the absolute reduction in lesion count after 2 weeksis at least twice the absolute reduction in lesion count after about 4weeks of treatment.

Yet another embodiment of this application is a first-line treatmentregimen for the therapeutic treatment of rosacea, including topicallyapplying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 1% to about 10% benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, to achieve, in a groupof such subjects, a primary measure of success of at least about 9%,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition and/or in said regimen, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 2 weeks and wherein the primary measure of success isdefined as a 2-grade improvement in Investigator Global Assessment (IGA)of clear or almost clear.

Yet another exemplary embodiment of this application is a first-linetreatment regimen for the therapeutic treatment of rosacea, the regimencomprising topically applying to the skin of a subject in need of saidtreatment a pharmaceutical composition, the pharmaceutical compositioncomprising about 1% to about 10% benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient, toachieve, in a group of such subjects, a secondary measure of success ofat least about 40%, wherein the benzoyl peroxide is the only activeingredient in said pharmaceutical composition and/or in said regimen,wherein said pharmaceutical composition is applied once daily for aperiod of at least about 2 weeks and wherein the secondary measure ofsuccess is defined as a percentage decrease the in the number ofinflammatory lesions.

Yet another exemplary embodiment of this application is a treatmentregimen for the therapeutic treatment of rosacea, the regimen comprisingtopically applying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 1% to about 10% benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, to achieve, in a groupof such subjects, wherein the pharmaceutical composition is physicallyand/or chemically stable for a period of at least about 12 weeks.

In some embodiments, said rosacea is papulopustular rosacea (i.e.,inflammatory rosacea; Rapini et al. (2007). Dermatology: 2-Volume Set.St. Louis: Mosby and James, William et al. (2005). Andrews' Diseases ofthe Skin: Clinical Dermatology. (10th ed.). Saunders p. 245).

Yet another embodiment of this application is a pharmaceuticalcomposition for use as a medicament for the treatment rosacea, thepharmaceutical composition comprising from about 1% to about 10% benzoylperoxide as an active ingredient, preferably about 2.5% w/w to about 10%w/w, preferably about 3% w/w to about 5% w/w of benzoyl peroxide, morepreferably about 5% benzoyl peroxide, and a pharmaceutically acceptablecarrier or excipient, wherein said pharmaceutical composition is appliedonce daily for a period of at least about 2 weeks, at least about 4weeks, at least about 8 weeks or at least about 12 weeks. Thepharmaceutical composition can include benzoyl peroxide as the onlyactive ingredient, and the benzoyl peroxide can be the sole activeingredient administered to the subject in need of said treatment duringthe duration of the regimen. The pharmaceutical composition can be usedas a medicament in the first-line treatment of rosacea.

Yet another embodiment of this application is use of a pharmaceuticalcomposition for the treatment of rosacea, the pharmaceutical compositioncomprising from about 1% to about 10% benzoyl peroxide as an activeingredient, preferably about 2.5% w/w to about 10% w/w, preferably about3% w/w to about 5% w/w of benzoyl peroxide, more preferably about 5%benzoyl peroxide, and a pharmaceutically acceptable carrier orexcipient, wherein said pharmaceutical composition is applied once dailyfor a period of at least about 2 weeks, at least about 4 weeks, at leastabout 8 weeks or at least about 12 weeks. The pharmaceutical compositioncan include benzoyl peroxide as the only active ingredient, and thebenzoyl peroxide can be the sole active ingredient administered to thesubject in need of said treatment during the duration of the regimen.The pharmaceutical composition can be used in the first-line treatmentof rosacea.

Yet another embodiment of this application is a pharmaceuticalcomposition for use as a medicament for providing early onset of actionin the therapeutic treatment rosacea, the pharmaceutical compositioncomprising from about 1% w/w to about 10% w/w benzoyl peroxide,preferably about 2.5% w/w to about 10% w/w, preferably about 3% w/w toabout 5% w/w benzoyl peroxide, more preferably about 5% w/w benzoylperoxide, as an active ingredient, and a pharmaceutically acceptablecarrier or excipient, wherein the benzoyl peroxide is the only activeingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 2, 4, 8 or 12 weeks, wherein a primary measure of success ina group of subject is at least about 9% after about 2 weeks or asecondary measure of success in a group of such subjects is at leastabout 40% after at least about 2 weeks, wherein the primary measure ofsuccess is defined as a 2-grade improvement in Investigator GlobalAssessment (IGA) of clear or almost clear wherein the second measure ofsuccess is defined as mean inflammatory lesion count percent reductionfrom baseline. The benzoyl peroxide can be the sole active ingredientadministered to the subject in need of said treatment during theduration of the regimen. The pharmaceutical composition can be used inthe first-line treatment of rosacea.

Yet another embodiment of this application is use of a pharmaceuticalcomposition for providing early onset of action in the treatment ofrosacea, the pharmaceutical composition comprising from about 1% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, preferably fromabout 2.5% w/w to about 10% w/w benzoyl peroxide, preferably 3% w/w toabout 5% w/w benzoyl peroxide, more preferably 5% w/w benzoyl peroxide,and a pharmaceutically acceptable carrier or excipient, wherein thebenzoyl peroxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 2, 4, 8 or 12 weeks, wherein aprimary measure of success in a group of subject is at least about 9%after about 2 weeks or a secondary measure of success in a group of suchsubjects is at least about 40% after at least about 2 weeks, wherein theprimary measure of success is defined as a 2-grade improvement inInvestigator Global Assessment (IGA) of clear or almost clear whereinthe second measure of success is defined as mean inflammatory lesioncount percent reduction from baseline. The benzoyl peroxide can be thesole active ingredient administered to the subject in need of saidtreatment during the duration of the regimen. The pharmaceuticalcomposition can be used in the first-line treatment of rosacea.

In some embodiments, the adverse effects after topical administration ofBPO are comparable to the adverse effects after topical administrationof a vehicle, and in some embodiments, the adverse effects after topicaladministration of BPO are less than the adverse effects after topicaladministration of a vehicle. In other embodiments, the number of rosaceapatients demonstrating no or almost no subcutaneous reactions aftertreatment with BPO increases weekly despite prolonged, weekly use of BPOin the treatment of rosacea.

In some further embodiments, the composition further comprises at leastone non pharmaceutical active additive selected from the groupconsisting of chelating agents, antioxidants, sunscreens, preservatives,fillers, electrolytes, humectants, dyes, mineral or organic acids orbases, fragrances, essential oils, moisturizers, vitamins, essentialfatty acids, sphingolipids, self-tanning compounds, calmatives andskin-protecting agents, pro-penetrating agents and gelling agents, or amixture and/or combination thereof.

In other embodiments, the composition is formulated into a topicallyapplicable, physiologically acceptable medium comprising of: (a) atleast one member selected from the group consisting of water, alcohols,oils, fatty substances and waxes; and (b) at least one additive selectedfrom the group consisting of chelating agents, antioxidants, sunscreens,preservatives, fillers, electrolytes, humectants, dyes, mineral acids,mineral bases, organic acids, organic bases, fragrances, essential oils,moisturizers, vitamins, essential fatty acids, sphingolipids,self-tanning compounds, calmatives, skin-protecting agents,pro-penetrating agents, gelling agents, emulsifiers, co-emulsifiers, andmixtures and/or combinations thereof.

In some embodiments the composition is formulated as an emulsion(including an oil-in-water emulsion, a water-in-oil emulsion, multipleemulsions and microemulsions). In other embodiments, the composition isformulated as a cream.

The compositions described in exemplary embodiments herein arepharmaceutical compositions, and especially dermatological compositions,which can be in any galenical form conventionally used for topicalapplication. By addition of a fatty or oily phase, they can also be inthe form of dispersions of the lotion or serum type, emulsions of liquidor semi-liquid consistency of the milk type obtained by dispersing afatty phase in an aqueous phase (O/W) or conversely (W/O), orsuspensions or emulsions of soft, semiliquid or solid consistency of thecream, gel or ointment type, or alternatively multiple emulsions (W/O/Wor O/W/O), microemulsions, microcapsules, microparticles and/orvesicular dispersions of ionic and/or nonionic type, and/or wax/aqueousphase dispersions. These compositions are formulated according to theusual methods.

In further embodiments, the composition comprises, as a singlepharmaceutical active agent, benzoyl peroxide in a solid form, fortopical use in the treatment of rosacea, is an oil in water emulsioncomprising a polyoxylstearate and a glycerylstearate. Various methodsfor the preparation of the BPO-containing compositions are described inU.S. Application Publication Nos. 2010/0016443, 2017/0281571 and2018/0147165 and U.S. Pat. No. 9,687,465.

In some embodiments, the ratio of said polyoxylstearate to saidglycerylstearate is in the range of about 0.1:10 to about 10:0.1.

In yet further embodiments, said polyoxylstearate is selected from thegroup consisting of Polyoxyl-8 stearate, Polyoxyl-20 stearate,Polyoxyl-40 stearate, Polyoxyl-100 stearate and combinations and/ormixtures thereof.

In further embodiments, said glycerylstearate is selected from the groupconsisting of glyceryl mono-stearate, glyceryl di-stearate andcombinations and/or mixtures thereof.

In other embodiments, said polyoxylstearate in said composition is inthe range of from about 0.1% w/w to about 30% w/w.

In further embodiments, the amount of said glycerylstearate in saidcomposition is in the range of from about 0.1% w/w to about 30% w/w.

In other embodiments, said composition further comprises at least onefatty alcohol.

In other embodiments, said at least one fatty alcohol is selected fromthe group consisting of octyl alcohol, 2-ethyl hexanol. nonyl alcohol,decyl alcohol, undecanol, dodecyl alcohol, tridecyl alcohol, tetradecylalcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol,heptadecyl alcohol, cetostearyl alcohol, stearyl alcohol, isostearylalcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol,elaidolinolenyl alcohol, ricinoleyl alcohol, nonadecyl alcohol,arachidyl alcohol, heneicosyl alcohol. behenyl alcohol, erucyl alcohol,lignoceryl alcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol,myricyl alcohol, melissyl alcohol, geddyl alcohol, cetearyl alcohol andcombinations and/or mixtures thereof.

In further embodiments, the amount of said at least one fatty alcohol insaid composition is in the range of from about 0.2% w/w to about 50%w/w.

In yet other embodiments, said composition further comprises apolyacrylic acid homopolymer or copolymer.

In other embodiments, said oil in said oil in water emulsion is selectedfrom the group consisting of paraffin oil, isopropyl myristate,caprylic/capric triglyceride, squalane, squalene, almond oil, castoroil, olive oil, jojoba oil, sunflower oil, soybean oil, grape seed oil,dimethicone, cyclomethicone and combinations and/or mixtures thereof.

In further embodiments, said oil in present in the composition in anamount in the range of from about 0.05% w/w to about 50% w/w.

In some embodiments, said water in said oil in water emulsion furthercomprises at least one water soluble humectant.

In other embodiments, said at least one water soluble humectant isselected from the group consisting of propylene glycol, glycerin,polyethylene glycol-X and combinations and/or mixtures thereof, where Xis in the range of from about 200 to about 10,000.

In some embodiments, the composition comprises said solid BPO in acontrolled and/or slowed release drug delivery system. In furtherembodiments, said controlled and/or slowed release drug delivery systemis an encapsulation in a microcapsule, wherein said solid BPO isembedded in said microcapsule. When referring to a “controlled and/orslowed release drug delivery system” it should be understood to relateto a delivery system (which in the present application is a topicaldelivery system) that enables the release of the pharmaceutical activeagent in predetermined amounts over a specified period. In someembodiments, said system is a core-shell system of a microcapsule and/ora porous matrix structure, such as, for example, a microsponge. The term“embedded” should be understood to encompass an inert system thatprovides a barrier between the pharmaceutical active agent, i.e. BPO,and its surrounding environment in the composition. In some embodiments,said agent is entrapped and/or encapsulated in said controlled releasesystem.

In some embodiments, said core of said microcapsule comprises orconsists of said solid BPO.

In some further embodiments, said microcapsules are a core shellmicrocapsule. The shell comprises at least one inorganic polymer. Insome other embodiments, said inorganic polymer of said shell is a metaloxide or semi-metal oxide shell (layer).

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising orconsisting of solid BPO.

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising solidBPO is prepared by a process comprising the steps of:

(a) contacting a solid BPO particulate matter with an ionic additive andan aqueous medium to obtain a dispersion of said particulate matterhaving positive charges on its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide layer thereon thereby to obtain particulatematter coated by a metal oxide coating layer;

(c) repeating step (b) at least 4 more times: and

(d) aging said coating layer.

As used herein, the term “solid BPO particulate matter” refers to asolid BPO having solubility in water of less than about 1% w/w,typically less than about 0.5% and at times less than about 0.1% w/w atroom temperature (about 20° C.). The “solid BPO particulate matter”constitutes the “core” of the particles obtained by the process. Thesolid BPO particulate matter, is, in some embodiments, in such a stateof subdivision that it can be suspended in water, e.g., in the form of afinely-divided powder having a D₉₀ (see definition below), in someembodiments in the range of from about 0.3 to about 50 microns. Such aparticulate matter can be readily suspended in an aqueous systems bystirring, with or without the aid of a surfactant.

The terms “solid BPO particulate matter” and “particulate matter” willbe used interchangeably.

In the present application, the terms “layer”, “coating” or “shell” andsimilar terms, refer to a layer of metal oxide or semi-metal oxideformed around a particle or particulate matter. The layer or coatingneed not always be complete or uniform and need not necessarily lead tocomplete coverage of the particulate matter or particle surface. It isappreciated that upon repetition of the coating steps as the coatingprocess proceeds a more uniform coating and more complete coverage ofthe particulate matter is obtained.

The term “dispersion,” as used herein, in step (a) of the process refersto a solid dispersion of the particulate matter in the aqueous medium.Step (a) of the process can further comprise reducing the particle sizeof the particulate matter to the desired particle size, for example, bymilling or homogenization.

The core (i.e., solid, BPO particulate matter) can be of any shape, forexample, rod-like, plate-like, ellipsoidal, cubic, spherical shape,combinations thereof and the like.

Reference to the size of particles will be made through their D₉₀, whichmeans that about 90% of the particles have the stated dimension or less(measured by volume). Thus, for example, for spherical particles statedto have a diameter of about 10 micrometer (“microns”), this means thatthe particles have a D₉₀ of about 10 microns. The D₉₀ can be measured bylaser diffraction. For particles having a shape other than spheres, theD₉₀ refers to the mean average of the diameter of a plurality ofparticles.

In the case of cores having a spherical shape, the D₉₀ can be in therange of from about 0.3 to 90 microns, in some embodiments from about0.3 to about 50 microns, in some other embodiments from about 1 to about50 microns, in some further embodiments from about 5 to about 30microns. By the term “D₉₀ can be in the range of from about 0.3 micronsto about 90 microns” is meant that about 90% by volume of the particles(in this case the particle's core) can be less than or equal to a valuein the range of from about 0.3 microns to about 90 microns.

For generally cubic-shaped cores or cores having a shape resembling thatof a cube, the mean size of a side can be in the range of from about 0.3to about 80 microns, in some embodiments from about 0.3 to about 40microns, in some further embodiments from about 0.8 to about 40 microns,in some further embodiments from about 4 to about 15 microns.

For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, thelargest dimension (that of the longest axis) is typically in the rangeof from about 10 to about 100 microns, in some embodiments from about 15to about 50 microns; and the smallest dimension is typically in therange of from about 0.5 to about 20 microns, in some further embodimentsfrom about 2 to about 10 microns.

As used herein, unless otherwise indicated, the term “particle” refersto the metal oxide or semi-metal oxide coated particulate matter.

It is appreciated that some of the particles obtained by the process canat times be formed from two or more original particles of the solid BPOparticulate and can accordingly include at times more than one core,such cores being separated from each other by a metal oxide region.

The weight of the solid BPO particulate (core material) based on thetotal weight of the particle can be in the range of from about 99% w/wto about 50% w/w, in some embodiments in the range of from about 97% w/wto about 50% w/w. The core material can be in a crystalline form,amorphous form, or combination thereof. The core material can be acosmetic, pharmaceutical or an agrochemical active ingredient.

EXEMPLARY EMBODIMENTS

BPO-containing compositions were prepared following the variouspreparation methods described in U.S. Application Publication Nos.2010/0016443, 2017/0281571 and 2018/0147165 and U.S. Pat. No. 9,687,465,the contents of which are incorporated herein, by reference, in theirentirety.

Example 1: Efficacy Study of BPO as First-Line Treatment of Rosacea

Description: A multi-center, double-blind, randomized,vehicle-controlled, dose-range study of encapsulated 5% benzoyl peroxide(E-BPO) Cream and vehicle cream was performed to assess the efficacy andsafety of E-BPO compared to vehicle. Study duration was 12 weeks andincluded approximately 350 male and female patients afflicted withpapulopustular rosacea. Patients were at least 18 years of age, and metthe inclusion/exclusion criteria described herein.

Dosing: Patients were randomized in a 2:1 ratio to the study product orvehicle treatment group, respectively. Patients applied the studyproduct once daily for 12 weeks on the face (chin, left cheek, rightcheek, nose, left forehead and right forehead) in a thin layer toprovide even distribution, and avoid the eyes, lips, inside the nose,mouth and all mucous membranes.

Clinical and Safety Evaluations will be performed at:

1. Visit 1/Screening

2. Visit 2/Baseline, Day 1

3. Visit 3/Week 2, Day 15 (±3 Days)

4. Visit 4/Week 4, Day 29 (±3 Days)

5. Visit 5/Week 8, Day 57 (±3 Days)

6. Visit 6/Week 12, Day 85 (±4 Days)/End of Treatment/End of Study)

Patients were admitted into the study after meeting allinclusion/exclusion criteria, including a clinical diagnosis of rosaceaand after written informed consent has been obtained. Subjects withsevere rosacea who are appropriate for systemic treatment need to becounseled regarding their treatment options by the PrincipalInvestigator. At each visit, a 5-point IGA scale of rosacea; rosaceaerythema, and telangiectasia; and inflammatory (papules, pustules)lesion counts were performed and recorded.

Safety was assessed at all visits, and will include monitoring of localadverse experiences, Investigator Cutaneous Safety Assessment rating ofdryness and scaling and Local Tolerability Assessment rating of itchingand burning/stinging on a scale ranging from 0 (None) to 3 (Severe);patients complete a Patient Reported Outcomes (PRO) questionnaire atVisit 2, 3, 4, 5 and 6 and Rosacea Quality of Life Questionnaire(RosaQoL) at Baseline and Visit 6 or at early termination. Standardizedphotography of facial rosacea at Visit 2, 3, 4, 5 and 6 was performed atselect site(s).

In addition to IGA, at each visit, the following safety measures wererecorded: monitoring for any AE (adverse effects) including local andsystemic; investigator Cutaneous Safety Assessment rating of erythema,dryness and scaling and Local Tolerability Assessments rating of itchingand burning/stinging on a scale ranging from 0 (None) to 3 (Severe).

Urine pregnancy tests were performed on females of child-bearingpotential at Screening, Baseline and every 4 weeks during study or atearly termination. Regardless of the duration of the study, patientsthat exhibit serious adverse event (SAE) were followed up until the SAEresolved based on investigator's medical judgement.

Evaluation of efficacy: The first application of the test product wasapplied at the investigational site at the end of the Baseline visit(Day 0) under the supervision and instruction of the designatedinvestigational site staff. The investigator performed the InvestigatorGlobal Assessment (IGA) and inflammatory lesion (papules and pustules)counts at Screening, Baseline, and Weeks 4, 8, and 12 (end of study) anderythema and telangiectasia assessments at Baseline, and Weeks 4, 8, and12 (end of study). The evaluator also assessed local application siteirritation (dryness, scaling, pruritus, stinging and burning) atBaseline and Weeks 2, 4, 8 and 12 (end of study). At selectedinvestigational site(s), standardized photography of facial rosacea alsowas performed at Baseline and Week 8 and 12 (end of study).

The absolute change (primary measure of success) and percent change(secondary measure of success) from baseline of inflammatory lesions wasderived for each patient at Weeks 2, 4, 8 and 12. The IGA was recordedfor each patient at Baseline, Weeks 2, 4, 8 and 12. Weeks 2, 4, 8 and 12with a patient were considered a success for those visits if the IGA wasat least 2 grades less than baseline and are Clear or Almost Clear. Datafrom two sets of experiments—Drug 01+Vehicle 01 and Drug 02+Vehicle02—are included herewith for each measurement

Safety Assessments: Safety was evaluated by tabulations of adverseevents (AEs), Cutaneous Safety Assessments for dryness and scaling,assessments for scores (erythema and telangiectasia) and Patient GlobalImpression of Treatment Side-Effects (PGI-SE) will be presented withdescriptive statistics at Baseline and at the scheduled study visits.Frequencies and percentages for each outcome category will be includedin these statistics.

Results:

Baseline Characteristics:

The Baseline characteristics were similar among the treatment groups.Patients selected for the treatment groups of this study suffered frommoderate and severe rosacea, with a numerically higher percentage ofsubjects suffering from moderate rosacea. The baseline numericalpercentage of treatment groups suffering from moderate and severerosacea were similar for 5% E-BPO Cream and for Vehicle Cream.

Primary Efficacy Analyses:

The proportions of subjects with a primary measure of success (definedas a 2-grade improvement in the IGA relative to Baseline at Weeks 2, 4,7 and 12, with an IGA of clear or almost clear) are shown in Tables 1Aand 1B, and FIG. 1.

The mean percentage of patients (average value from two studies)achieving clear to almost clear grade after treatment with E-BPO 5%cream were: about 11.35% (week 2), about 25.75% (week 4), about 41.8%(week 8) and about 46.8% (week 12). In comparison, the correspondingmean percentage of patients achieving clear to almost clear grade aftertreatment with the vehicle cream were: about 4.3% (week 2), about 10.3%(week 4), about 20.9% (week 8) and about 21% (week 12).

As seen from these results, topical application of BPO is highlyeffective as a first-line treatment of rosacea, including up to about50% of patients achieving a clear to almost clear grade after 12 weeksof treatment with 5% E-BPO cream, which is significantly greater thanthe effect observed after treatment with vehicle cream.

TABLE 1A Improvement in IGA Difference IGA (Drug − Weekly Change WeekDrug 01 Vehicle 01 Vehicle) P-Value Drug Vehicle 2 9.50 3.10 6.40 0.0099.50 3.10 4 25.40 6.50 18.90 <0.001 15.90 3.40 8 39.60 15.80 23.80<0.001 14.20 9.30 12 43.50 16.10 27.40 <0.001 3.90 0.30

TABLE 1B Improvement in the IGA Difference IGA (Drug − Weekly ChangeWeek Drug 02 Vehicle 02 Vehicle) P-Value Drug Vehicle 2 13.20 5.50 7.700.017 13.20 5.50 4 26.10 14.10 12.00 0.009 12.90 8.60 8 44.00 26.0018.00 0.006 17.90 11.90 12 50.10 25.90 24.20 <0.001 6.10 −0.10

Secondary Efficacy Analyses:

The proportions of subjects with a secondary measure of success (definedas change in the mean inflammatory lesion count from Baseline to Weeks2, 4, 8 and 12) are shown in Tables 2A, 2B, 3A and 3B, and FIGS. 2 and3.

The mean percentage improvement values of E-BPO 5% cream were: about42.5% (week 2), about 58% (week 4), about 68% (week 8) and about 69%(week 12). In comparison, the mean percentage improvement values of thevehicle cream were: about 24% (week 2), about 36% (week 4), about 42.6%(week 8) and about 42.4% (week 12).

As seen from these results, topical application of BPO is highlyeffective as a first-line treatment of rosacea, including over 69%decrease in inflammatory lesions after at least 12 weeks of treatment,which is more than 1.5× the effect observed after treatment with vehiclecream.

TABLE 2A Percent change in inflammatory lesion count % Change inDifference Lesion Count (Drug − Weekly Change Week Drug 01 Vehicle 01Vehicle) Drug Vehicle 2 −41.34 −22.85 −18.49 −41.34 −22.85 4 −58.31−35.40 −22.91 −16.97 −12.55 8 −66.94 −41.74 −25.20 −8.63 −6.34 12 −68.20−38.78 −29.42 −1.26 2.96

TABLE 2B Percent change in inflammatory lesion count % Change inDifference Lesion Count (Drug − Weekly Change Week Drug 02 Vehicle 02Vehicle) Drug Vehicle 2 −43.69 −25.36 −18.33 −43.69 −25.36 4 −57.98−37.25 −20.73 −14.29 −11.89 8 −68.74 −43.46 −25.28 −10.76 −6.21 12−69.40 −46.00 −23.40 −0.66 −2.54

The absolute reduction in inflammatory lesion count also demonstratesthe enhanced efficacy of using BPO as a first-line treatment forrosacea. As seen from the results in Tables 3A and 3B, and illustratedin FIG. 3, topical application of 5% BPO is highly effective as afirst-line treatment of rosacea, decreasing the absolute lesion count byat least 1.5× the decrease observed after treatment with vehicle cream.

TABLE 3A Absolute change in inflammatory lesion count Lesion CountDifference (number) (Drug − Weekly Change Week Drug 01 Vehicle 01Vehicle) P-Value Drug Vehicle 2 −10.50 −5.50 −5.00 <0.001 −10.50 −5.50 4−14.60 −8.70 −5.90 <0.001 −4.10 −3.20 8 −16.80 −10.60 −6.20 <0.001 −2.20−1.90 12 −17.40 −9.50 −7.90 <0.001 −0.60 1.10

TABLE 3B Absolute change in inflammatory lesion count Lesion CountDifference (number) (Drug − Weekly Change Week Drug 02 Vehicle 02Vehicle) P-Value Drug Vehicle 2 −13.00 −8.00 −5.00 <0.001 −13.00 −8.00 4−16.70 −10.50 −6.20 <0.001 −3.70 −2.50 8 −20.00 −12.40 −7.60 <0.001−3.30 −1.90 12 −20.30 −13.30 −7.00 <0.001 −0.30 −0.90

Early Onset of Action:

The results in Tables 1A to 3B and FIGS. 1 to 3 also demonstrate theearly onset of action in the BPO-treatment of rosacea. For example, asshown in Tables 2A and 2B, on average, an about 40% decrease ininflammatory lesions is observed after only 2 weeks of treatmentcompared to less than about 25% decrease in inflammatory lesions in thesame time period after treatment with vehicle. Early onset is alsodemonstrated by over about 58% decrease in inflammatory lesions in 4weeks, and almost about 70% decrease in inflammatory lesions in 8 weeks,compared to only about 40% decrease in weeks 4 and 8 with vehicle creamtreatment. Surprisingly, the effect achieved after 8 weeks of treatmentis comparable to the effect achieved after 12 weeks of treatmentindicating an onset response at an early point in time during thetreatment schedule, and reaching a plateau after 8 weeks of treatment.Similar results are observed for IGA and absolute change in lesion countin Tables 1A, 1B, 3A and 3B. That is, surprisingly, the highest effectswere observed after 2 weeks of treatment, and the difference in thechanges observed after 8 weeks and after 12 weeks of treatment wasnegligible.

Recently, clinical studies on topical treatment of inflammatory lesionsof rosacea using 1% ivermectin cream have been submitted to FDA forapproval of the Galderma product SOOLANTRA® (available athttps://www.accessdata.fda.gov/drugsatfa_docs/nda/2014/206255Orig1s000StatR.pdf,last accessed Jul. 4, 2019). The results after 2 weeks and 8 weeks oftreatment with SOOLANTRA® available at Section 3.2.7 of this study arereproduced below. The “time to onset” of efficacy was determined using aconditional backward stepwise testing approach of the co-primaryefficacy endpoints for the different weeks (Weeks 12, 8, 4 and 2). Asshown in Table 13 of the SOOLANTRA® study, reproduced below, SOOLANTRA®was statistically superior (α=0.05) to vehicle on the co-primaryendpoints starting from Week 4. That is, the fastest onset results inthe SOOLANTRA® clinical study having statistical significance (α<0.05)were observed after 4 weeks of treatment by a 10% success in IGA.

TABLE 13 Results for the Co-Primary Efficacy Endpoints over Time (ITT,LOCF) IGA Success⁽¹⁾: n (%) Absolute Change in Inflammatory LesionCounts: Mean (SD) SOOLANTRA Vehicle P-value⁽²⁾ SOOLANTRA VehicleP-value⁽³⁾ Study 18170 N = 451 N = 232 N = 451 N = 232 Week 12 173(38.4%) 27 (11.6%) <0.001 20.5 (16.0) 12.0 (13.5) <0.001 Week 8 104(23.1%) 23 (9.9%)  <0.001 17.9 (14.8) 10.1 (14.0) <0.001 Week 4  49(10.9%) 13 (5.6%)  0.021 13.6 (14.9)  7.7 (12.3) <0.001 Week 2 17 (3.8%)5 (2.2%) 0.267  8.8 (13.4)  5.1 (11.1) <0.001 Study 18171 N = 459 N =229 N = 459 N = 229 Week 12 184 (40.1%) 43 (18.8%) <0.001 22.2 (14.9)13.4 (14.5) <0.001 Week 8 126 (27.5%) 28 (12.2%) <0.001 19.8 (14.4) 11.2(13.3) <0.001 Week 4  54 (11.8%) 13 (5.7%)  0.014 14.3 (13.8)  7.8(11.9) <0.001 Week 2 16 (3.5%) 6 (2.6%) 0.551  9.1 (12.3)  6.3 (11.7)0.006 Source: Reviewer's Analysis ⁽¹⁾Success is defined as achieving anIGA score of 0 (Clear) or 1 (Almost Clear). ⁽²⁾P-value claculated from aCMH test stratified by analysis centers. ⁽³⁾P-value calculated based onan ANCOVA model with baseline lesion count, treatment, and analysiscenters as factors.

In comparison, and quite surprisingly, in the BPO-based treatment ofrosacea, as described in the subject application, the fastest onsetsuccess was obtained by about 25% success in IGA after only 4 weeks oftreatment, which is more than twice the effect observed after treatmentwith SOOLANTRA® for four weeks. In fact, fastest onset success can beachieved even earlier, as shown by an about 10% success in IGA after 2weeks of BPO-treatment. The difference in the results achieved using thetwo treatment methods is shown in FIG. 4.

Data shown in Tables 1A, 1B, 2A, 2B, 3A and 3B also include thecorresponding P-Values. The P-value is a statistical calculation of thedifference between the drug and the vehicle (placebo). A P-Value <0.05indicates statistical superiority of the drug over the vehicle. In orderfor a drug to be approved, the P-Value at week 12 must be <0.05.Surprisingly, as shown in the tables of this application, the P-Values<0.05 at all timepoints—2 weeks, 4 weeks, 8 weeks and 12 weeks. TheP-values from the clinical studies of BPO-based treatment of rosacea, asdescribed in this application, is another, surprising indication of thefast onset activity of the method described herein.

The results in the subject application indicate that BPO-treatment ofrosacea should be recommended as the first line treatment of rosacea,contrary to known methods of using BPO in combination with other activeagents or using BPO as only a second-line or even later-stage treatment.Moreover, such early onset of action can improve patient compliance totreatment protocols, resulting in an even higher percentage of success.

Subcutaneous Reaction:

BPO is a strong oxidizer, and would be expected to result in asignificant increase in subcutaneous reaction, such as dryness, scaling,itching, burning and stinging, in patients being treated for rosaceawith a BPO-containing formulation. As demonstrated in U.S. ApplicationPublication Nos. 2010/0016443, 2017/0281571 and 2018/0147165 and U.S.Pat. No. 9,687,465, encapsulation of BPO can reduce the irritationassociated with BPO. Thus, resulting in only a minor increase insubcutaneous reactions compared to the use of un-encapsulated BPO.Surprisingly, however, following the use of BPO in the studies describedherein, the number of rosacea patients reporting no and/or almost nosubcutaneous reactions increased as the use of the drug continued.Moreover, the percentage of patients using the drug reporting nosubcutaneous reactions was comparable, and for some conditions,surprisingly, higher than the percentage of patients using the vehicle.That is, the treatment regimen described herein has an adverse eventsvalue similar to, or in some instances, surprisingly, even less than,the adverse events value of a vehicle control.

Table 4A and 4B list the percentage of patients reporting nosubcutaneous reactions at 2, 4, 8 and 12 weeks compared to thepercentage of patients reporting no subcutaneous reaction at baseline.

TABLE 4A Percentage of Patients Reporting No Subcutaneous ReactionsDryness Scaling Itching Burning/Stinging Drug Vehicle Drug Vehicle DrugVehicle Drug Vehicle Week 01 01 01 01 01 01 01 01 Baseline 45.6 46.066.5 68.1 35.6 41.6 52.7 49.6 2 61.4 58.6 76.7 68.5 51.7 55.0 56.8 52.74 64.4 58.2 83.1 76.4 63.1 59.1 67.8 63.6 8 71.1 58.9 83.3 72.9 69.761.7 75.0 69.2 12 71.5 65.4 84.2 72.9 68.8 52.3 74.2 70.1

TABLE 4B Percentage of Patients Reporting No Subcutaneous ReactionsDryness Scaling Itching Burning/Stinging Drug Vehicle Drug Vehicle DrugVehicle Drug Vehicle Week 02 02 02 02 02 02 02 02 Baseline 48.4 48.866.1 66.1 47.6 52.9 64.1 71.9 2 55.1 65.8 78.2 82.5 60.5 65.0 63.8 70.84 56.8 64.7 81.3 80.7 63.5 65.5 75.1 79.8 8 63.1 63.5 85.4 81.7 71.269.6 77.7 80.0 12 64.8 62.3 82.8 81.6 71.2 71.9 78.5 78.9

Although the exemplary embodiments of the present disclosure have beendescribed in detail with reference to the accompanying examples anddrawings, the present disclosure is not limited thereto and can beembodied in many different forms without departing from the technicalconcept of the present disclosure. Therefore, the exemplary embodimentsof the present disclosure are provided for illustrative purposes onlyand are not intended to limit the technical concept of the presentdisclosure. The protective scope of the present disclosure should beconstrued based on any appended claims and combinations thereof, and allthe technical concepts in the equivalent scope thereof should beconstrued as falling within the scope of the present disclosure. Asvarious changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense. Other embodiments within thescope of the claims herein will be apparent to one skilled in the artfrom consideration of the specification or practice of the exemplaryembodiments disclosed herein. It is intended that the specification beconsidered exemplary only, with the scope and spirit of the describedsubject matter being indicated by the claims.

What is claimed is:
 1. A treatment regimen for providing early onset ofaction in the therapeutic treatment of rosacea, the regimen comprisingtopically applying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 2.5% w/w to about 10% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, wherein said pharmaceutical composition isapplied once daily for a period of at least about 2, 4, 8 or 12 weeks,wherein said pharmaceutical composition is a cream or an emulsion,wherein a primary measure of success in a group of subjects is at leastabout 9% to about 40%, and wherein the primary measure of success isdefined as a 2-grade improvement in Investigator Global Assessment (IGA)and clear or almost clear.
 2. The treatment regimen of claim 1, whereinthe primary measure of success is at least about 9% after about 2 weeks.3. The treatment regimen of claim 1, wherein the primary measure ofsuccess is at least about 25% after about 4 weeks.
 4. The treatmentregimen of claim 1, wherein the primary measure of success is at leastabout 40% after about 8 weeks.
 5. The treatment regimen of claim 1,wherein the benzoyl peroxide is the sole active ingredient administeredto the subject in need of said treatment during the duration of theregimen.
 6. The treatment regimen of claim 1, wherein the pharmaceuticalcomposition comprises about 5% w/w of benzoyl peroxide.
 7. The treatmentregimen of claim 1, wherein the regimen is a first-line therapy for thetreatment of rosacea.
 8. The treatment regimen of claim 1, wherein therosacea is any of erythematotelengietatic, papulopustular, phymatous orocular rosacea.
 9. The treatment regimen of claim 1, wherein saidpharmaceutical composition is an extended release formulation, and thebenzoyl peroxide is encapsulated, microencapsulated, included in amicrosphere and/or including in a coating.
 10. The treatment regimen ofclaim 1, wherein said regimen has an adverse events values similar to orlower than the adverse events values of a vehicle control.
 11. Atreatment regimen for providing early onset of action in the therapeutictreatment of rosacea, the regimen comprising topically applying to theskin of a subject in need of said treatment a pharmaceuticalcomposition, the pharmaceutical composition comprising about 2.5% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is applied oncedaily for a period of at least about 2, 4, 8 or 12 weeks, wherein saidpharmaceutical composition is a cream or an emulsion, wherein asecondary measure of success in a group of such subjects is at leastabout 40% to at least about 65%, and wherein the second measure ofsuccess is defined as mean inflammatory lesion count percent reductionfrom baseline.
 12. The treatment regimen of claim 11, wherein thesecondary measure of success is at least about 40% after at least about2 weeks.
 13. The treatment regimen of claim 11, wherein the secondarymeasure of success is at least about 55% after at least about 4 weeks.14. The treatment regimen of claim 11, wherein the secondary measure ofsuccess is at least about 65% after at least about 8 weeks.
 15. Thetreatment regimen of claim 11, wherein the benzoyl peroxide is the soleactive ingredient administered to the subject in need of said treatmentduring the duration of the regimen.
 16. The treatment regimen of claim11, wherein the pharmaceutical composition comprises about 5% w/w ofbenzoyl peroxide.
 17. The treatment regimen of claim 11, wherein theregimen is a first-line therapy for the treatment of rosacea.
 18. Thetreatment regimen of claim 11, wherein the rosacea is any oferythematotelengietatic, papulopustular, phymatous or ocular rosacea.19. The treatment regimen of claim 11, wherein said pharmaceuticalcomposition is an extended release formulation, and wherein the benzoylperoxide is encapsulated, microencapsulated, included in a microsphereand/or included in a coating.
 20. The treatment regimen of claim 11,wherein said regimen has an adverse events values similar to or lowerthan the adverse events values of a vehicle control.
 21. A treatmentregimen for providing early onset of action in the therapeutic treatmentof rosacea, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 2.5% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is a cream or an emulsion, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 2, 4, 8 or 12 weeks, and wherein the absolute reduction inlesion count after about 2 weeks is at least twice the absolutereduction in lesion count after about 4 weeks of treatment.
 22. Thetreatment regimen of claim 21, wherein the benzoyl peroxide is the soleactive ingredient administered to the subject in need of said treatmentduring the duration of the treatment regimen.
 23. The treatment regimenof claim 21, wherein the pharmaceutical composition comprises about 5%w/w of benzoyl peroxide.
 24. The treatment regimen of claim 21, whereinthe regimen is a first line therapy for the treatment of rosacea. 25.The treatment regimen of claim 21, wherein the rosacea is any oferythematotelengietatic, papulopustular, phymatous or ocular rosacea.26. The treatment regimen of claim 21, wherein said pharmaceuticalcomposition is an extended release formulation, and wherein the benzoylperoxide is encapsulated, microencapsulated, included in a microsphereand/or included in a coating.
 27. The treatment regimen of claim 21,wherein said regimen has an adverse events values similar to or lowerthan the adverse events values of a vehicle control.
 28. The treatmentregimen of claim 21, wherein a primary measure of success in the groupof subjects is at least about 9% to about 40%, and wherein the primarymeasure of success is defined as a 2-grade improvement in InvestigatorGlobal Assessment (IGA) and clear or almost clear.
 29. The treatmentregimen of claim 21, wherein a secondary measure of success in the groupof subjects is at least about 40% to at least about 65%, and wherein thesecond measure of success is defined as mean inflammatory lesion countpercent reduction from baseline.